Neutrophils in tuberculosis: friend or foe?

Neutrophils are rapidly recruited to sites of mycobacterial infection, where they phagocytose bacilli. Whether neutrophils can kill mycobacteria in vivo probably depends on the tissue microenvironment, stage of infection, individual host, and infecting organism. The interaction of neutrophils with macrophages, as well as the downstream effects on T cell activity, could result in a range of outcomes from early clearance of infection to dissemination of viable bacteria together with an attenuated acquired immune response. In established disease, neutrophils accumulate in situations of high pathogen load or immunological dysfunction, and are likely to contribute to pathology. These activities may have clinical importance in terms of new treatments, targeted interventions and vaccine strategies.     

T-cell receptor revision: friend or foe?

T‐cell receptor (TCR) revision is a process of tolerance induction by which peripheral T cells lose surface expression of an autoreactive TCR, reinduce expression of the recombinase machinery, rearrange genes encoding extrathymically generated TCRs for antigen, and express these new receptors on the cell surface. We discuss the evidence for this controversial tolerance mechanism below. Despite the apparent heresy of post‐thymic gene rearrangement, we argue here that TCR revision follows the rules obeyed by maturing thymocytes undergoing gene recombination. Expression of the recombinase is carefully controlled both spatially and temporally, and may be initiated by loss of signals through surface TCRs. The resulting TCR repertoire is characterized by its diversity, self major histocompatibility complex restriction, self tolerance, and ability to mount productive immune responses specific for foreign antigens. Hence, TCR revision is a carefully regulated process of tolerance induction that can contribute to the protection of the individual against invading pathogens while preserving the integrity of self tissue.     

Host immune response in B-cell lymphomas: friend or foe?

The interaction of B-cell malignancies with the host immune system is a dynamic and bilateral process. Certain lymphomas more commonly arise within a background of autoimmunity or chronic infection. Initiation of these tumors is commonly reliant on antigenic stimulation and/or T-cell help. Apart from its tumor-fueling role, the host immune response plays a critical role in cancer immunosurveillance and immunoediting. The concept of immunoediting holds that the immune system sculpts the tumor's immunogenicity in a dynamic process that involves three essential phases: elimination, equilibrium, and escape. Data obtained by studying gene-targeted animals and human lymphomas that support the critical role of the immune response in the initiation, progression, and immunoediting of lymphoid malignancies are summarized here. A thorough understanding of this interaction will lead to the identification of more rational treatment targets and improved immunotherapies in B-cell lymphomas.     

Toll-like receptor 3 in viral pathogenesis: friend or foe?

Viral infections frequently induce acute and chronic inflammatory diseases, yet the contribution of the innate immune response to a detrimental host response remains poorly understood. In virus‐infected cells, double‐stranded RNA (dsRNA) is generated as an intermediate during viral replication. Cell necrosis (and the release of endogenous dsRNA) is a common event during both sterile and infectious inflammatory processes. The discovery of Toll‐like receptor 3 (TLR3) as an interferon‐inducing dsRNA sensor led to the assumption that TLR3 was the master sentinel against viral infections. This simplistic view has been challenged by the discovery of at least three members of the DExd/H‐box helicase cytosolic sensors of dsRNA that share with TLR3 the Toll–interleukin‐1 receptor (TIR) ‐adapter molecule TIR domain‐containing adaptor protein interferon‐β (TRIF) for downstream type I interferon signalling. Data are conflicting on the role of TLR3 in protective immunity against viruses in the mouse model. Varying susceptibility to infection and disease outcomes have been reported in TLR3‐immunodeficient mice. Surprisingly, the susceptibility to develop herpes simplex virus‐1 encephalitis in humans with inborn defects of the TLR3 pathway varies, and TLR3‐deficient humans do not show increased susceptibility to other viral infections. Therefore, a current challenge is to understand the protective versus pathogenic contribution of TLR3 in viral infections. We review recent advances in the identification of TLR3‐signalling pathways, endogenous and virus‐induced negative regulators of the TLR3 cascade, and discuss the protective versus pathogenic role of TLR3 in viral pathogenesis.     

Are reactive oxygen species involved in Alzheimer's disease?

Alzheimer's disease has a multifactorial pathogenesis. Among the various factors involved, this review examines, in particular, the possibility of oxidative stress, meaning an imbalance between the formation and spread of reactive oxygen species (ROS) and the antioxidant defenses. This theory is supported by the following observations: (a) the alteration of mitochondrial function, which is likely to lead to the electron leakage in the respiratory chain and the consequent formation of superoxide radicals; (b) the unbalanced high activity of superoxide dismutase and monoamine oxidase B which causes the production of more H₂O₂; (c) the alteration of iron homeostasis which, in combination with the superoxide and H₂O₂ gives rise to the most deleterious hydroxyl radicals; (d) the increased lipid peroxidation and membrane alterations; (e) the pro-aggregating effect of ROS on β/A4 protein and the C-terminal fragment of amyloid precursor (A4CT). Most of these changes are already present in the normal aging brain but are aggravated in AD presumably over a number of years. However, further investigations are needed to confirm these theories particularly regarding the alterations of another target of ROS, the proteins. Peroxidative stress is presumably present in the AD brain. This stress might not be a primary factor in the pathogenesis of AD, but a consequence of the tissue injury. In any case, it could contribute considerably to the pathology, in a vicious cycle of actions and reactions resulting in a critical mass of metabolic errors, responsible in the end for this disease.     

IL-17A in hepatitis B infection: friend or foe?

Hepatitis B virus (HBV) is one of the most prevalent and infectious agents that leads to liver disease in humans. Five clinical forms of HBV infection exist, including fulminant, acute, chronic, asymptomatic and occult. The chronic, asymptomatic and occult forms are long-term infections that can lead to hepatocellular carcinoma (HCC) and liver cirrhosis. The mechanisms responsible for progression of these forms of the infection to HCC and liver cirrhosis are not yet clearly understood or characterised. However, genetic and immunological parameters may play important roles in the disease. IL-17A is an important cytokine involved in early immune responses against fungal and bacterial infections, but its role in the response against viral infections is yet to be fully clarified. The crucial roles of IL-17A in the pathogenesis of autoimmune and destructive immune-related diseases have been documented and may provide insights into its functions during hepatitis infection. Therefore, the aim of this review was to address the recent information regarding the status and association of IL-17A during hepatitis B infection and its related disorders, including HCC and liver cirrhosis.     

T helper type 1 cells in asthma: friend or foe?

A large body of research supports a pathogenic role for T helper 2 cells in asthma, although T helper 1 cell-type responses may also contribute. Using the principle of T helper cell cross-regulation, investigators have attempted to regulate the pathological effects of T helper 2 cells using regimens that may promote T helper 1 cell-type inflammation. In this review, we propose that the use of factors that promote T helper 1 cell differentiation and activation to treat asthma may be counterproductive, and that alternate regulatory approaches should be explored.     

The complement system in the peripheral nerve: friend or foe?

The complement (C) system plays a central role in innate immunity and bridges innate and adaptive immune responses. A fine balance of C activation and regulation mediates the elimination of invading pathogens and the protection of the host from excessive C deposition on healthy tissues. If this delicate balance is disrupted, the C system may cause injury and contribute to the pathogenesis of various diseases, including neuropathies. Here we review evidence indicating that C factors and regulators are locally synthesized in the peripheral nerve and we discuss the evidence supporting the protective or detrimental role of C activation in health, injury and disease of the peripheral nerve.     

Role of interleukin-21 in HBV infection: friend or foe?

Interleukin (IL)-21, a cytokine produced by activated CD4⁺ T cells, has broad pleiotropic actions that affect the functions of a variety of lymphoid cells. The roles of IL-21 in modulating immunity to infections are currently being defined. Notably, IL-21-mediated cellular and humoral immune responses play an important role in determining the outcome of viral infection. This article reviews the current knowledge on the critical role of IL-21 in hepatitis B virus (HBV) infection. As a competent intermediary, IL-21 derived from virus-specific CD4⁺ T cells plays key roles in sustaining CD8⁺ T cells and promoting B-cell responses that are essential for effective viral control. However, as a mediator of inflammation, IL-21 is also involved in the development of HBV-induced liver cirrhosis and exacerbating liver injury. Overall, the current data point to IL-21 as an immunomodulatory cytokine in HBV infection. Immunotherapeutic strategies aimed at optimizing the beneficial effects of IL-21 in HBV infection may prove to be a rigorous challenge in the future, as they should foster the strengths of IL-21 while circumventing potential drawbacks.     

Th2-mediated anti-tumour immunity: friend or foe?

The concept that the immune system can recognise tumour cells and either eliminate them (tumour immune surveillance) or select for immunologically resistant variants (immunoediting) is gaining general acceptance by immunologists. In terms of an adaptive immune response to cancer, however, much of the research has focused on the response of cytotoxic CD8+ T lymphocytes to tumour-specific antigens and the production of Th1 cytokines by CD4+ and CD8+ T cells. In contrast, Th2-mediated immunity has traditionally been viewed as favouring tumour growth, both by promoting angiogenesis and by inhibiting cell-mediated immunity and subsequent tumour cell killing. While there is evidence that components of type 2 inflammation, such as B cells and interleukin-10, do promote tumour growth, there are also many studies demonstrating the anti-tumour activity of CD4+ Th2 cells, particularly in collaboration with tumour-infiltrating granulocytes, such as eosinophils. In this review, we examine all the components of type 2 immunity and their effects on tumour growth. Collectively, from this analysis, we conclude that there is a great potential for the development of Th2-mediated immunotherapies that harness the cytotoxic activity of eosinophils.     

Phosphorylcholine: friend or foe of the immune system?

Phosphorylcholine (PC) is a structural component of a variety of prokaryotic and eukaryotic pathogens. In some cases, PC in infectious agents can benefit the infected host due to its targeting by both the innate and adaptive immune responses. However, as discussed here, PC exhibits a surprising range of immunomodulatory properties that might be to the detriment of the host.     

Helminth infection in populations undergoing epidemiological transition: a friend or foe?

Helminth infections are highly prevalent in developing countries, especially in rural areas. With gradual development, there is a transition from living conditions that are dominated by infection, poor sanitation, manual labor, and traditional diet to a situation where burden of infections is reduced, infrastructure is improved, sedentary lifestyle dominates, and processed food forms a large proportion of the calorie intake. The combinations of some of the changes in lifestyle and environment are expected to result in alteration of the landscape of diseases, which will become dominated by non-communicable disorders. Here we review how the major helminth infections affect a large proportion of the population in the developing world and discuss their impact on the immune system and the consequences of this for other infections which are co-endemic in the same areas. Furthermore, we address the issue of decreasing helminth infections in many parts of the world within the context of increasing inflammatory, metabolic, and cardiovascular diseases.     

The role of microRNAs in respiratory viral infection: friend or foe?

MicroRNAs (miRNAs) have emerged as a class of regulatory RNAs in host–pathogen interactions. Aberrant miRNA expression seems to play a central role in the pathology of several respiratory viruses, promoting development and progression of infection. miRNAs may thus serve as therapeutic and prognostic factors for respiratory viral infectious disease caused by a variety of agents. We present a comprehensive review of recent findings related to the role of miRNAs in different respiratory viral infections and discuss possible therapeutic opportunities aiming to attenuate the burden of viral infections. Our review supports the emerging concept that cellular and viral‐encoded miRNAs might be broadly implicated in human respiratory viral infections, with either positive or negative effects on virus life cycle. Copyright © 2016 John Wiley & Sons, Ltd.